Current Dilemma in Hepatology: To Treat or Not to Treat All Patients with Hepatitis C Virus Infection

Douglas LaBrecque, M.D.
Zlatko Anguelov
University of Iowa Hospitals and Clinics

First Published: Summer 2002
Last Revised: September 2003
Peer Review Status: Internally Peer Reviewed

New facts:

Hepatitis C, caused by the hepatitis C virus (HCV), is currently the leading cause of liver transplantation. If the disease is left to run its natural course, the majority of people infected with HCV remain contagious throughout their lives due to unremitting viremia. In the later stages of the disease patients develop liver cirrhosis or, less frequently, hepatocellular carcinoma (HCC).

Genetic heterogeneity of HCV within the population is categorized by six major genotypes that show geographic variation. For example, approximately 70% of individuals with HCV in the U.S. have genotype 1 infection which, as compared with genotypes 2 and 3, is associated with lower response rates to antiviral therapy.

Diagnosis, monitoring, and treatment of patients with HCV and its chronic complications are expensive. Health care costs for HCV include managing patients with symptoms and other organ involvement, treating patients with antiviral agents, and managing end-stage liver disease, including liver transplantation. Reputable U.S. authors estimate that the annual cost for treating HCV infections will exceed one billion dollars by 2008, while another no less reputable group arrived at a dramatically higher figure, estimating that the annual cost had already passed $5 billion in 1997. In either case, costs will continue to rise as new treatment agents become available and untreated patients develop the complications of a more advanced disease.

In addition, studies of antiviral therapy cost-effectiveness have yet to be based on randomized clinical trials. Rather, they rely on decision-analysis models, which are construed from incomplete knowledge of the natural history of HCV infection and the assumption that a sustained virologic response (SVR) to therapy restores life expectancy to that of the general population. Indeed, accumulating evidence shows that an SVR may represent a cure in many cases.

Thus, high treatment costs and cost-effectiveness have imposed themselves as key factors in evaluating the management options available to physicians who treat patients with HCV. To understand why this is so, one should review the way HCV is transmitted, its pathogenesis and natural history, the reliability of liver histology as a predictor of progression to cirrhosis, and the variability in individual responses to HCV infection.

Figure 1: Histologic views of progression to cirrhosis

Figure 1A: Normal liver histology
Figure 1B: Early HCV-caused fibrosis
Figure 1C: Late stage of cirrhosis

Transmission. HCV enters a host via the skin or a mucous membrane. The most common means of infection is injection drug use, accounting for approximately 60% of new infections. Sexual transmission accounts for up to 20% of new cases of HCV infection. Additional risk factors, such as perinatal transmission, hemodialysis, occupational exposure, and household exposure to contaminated blood account for another 10% of cases. Currently, in 10% of people with HCV an obvious risk factor cannot be identified.

The current incidence of acute hepatitis C in the U.S. is declining. The decline began about 15 years ago as a result of reduced transmission among injection drug users and the use of second-generation anti-HCV testing to exclude potential blood donors who are infected. However, in spite of these measures, the prevalence of HCV is still rising. Given the large number of people who were infected with HCV before the introduction of blood donor testing for HCV and before the highly effective HIV-driven anti-injection drug use campaigns of the 1990s, this rise demonstrates the chronic, lifelong nature of HCV infection and the body's inability to rid itself of the virus on its own.

The host's immune response plays a key role in chronic hepatitis C pathogenesis. HCV elicits both humoral and cellular immune responses. The secretion of interleukin 2, interferon gamma, and tumor necrosis factor (TNF) has a direct antiviral effect and also stimulates the production of cytotoxic T cells that recognize and lyse cells infected with the virus. However, the immune response to HCV seems to be effective in only about 25% of infected individuals. These patients show a strong cellular response to HCV.

In the 75% of patients whose cellular immune response is ineffective in fully clearing the virus, the persistence of HCV infection produces liver injury, whereby cytotoxic T cells and cytokines, such as TNF-a, destroy infected hepatocytes, thus causing collateral damage to neighboring uninfected cells. The result of this immune overreaction against the liver leads to hepatic inflammation and fibrogenesis.

The development of fibrosis is the central event in chronic hepatitis C pathogenesis. Over time it leads to cirrhosis. The fatal consequence of cirrhosis is portal hypertension, the complications of which--variceal hemorrhage, ascites, or encephalopathy--ultimately kill hepatitis C patients. Thus, preventing the progression of fibrosis and the development of cirrhosis is a key goal in the management of HCV-infected people.

Studying the natural history of HCV infection is difficult due to the problematic nature of both prospective and retrospective studies. In a large cohort of seropositive HCV patients, approximately 75% were found to have HCV viremia, suggesting that 25% of those exposed cleared the infection spontaneously.

In general, studies reveal a slowly progressing disease leading to cirrhosis in approximately 20% of patients after 20 years. An apparent exception is an Irish study, which reported only 2.4% of patients with cirrhosis after an average of 17 years follow-up. However, another 15% of participants in that study had bridging fibrosis, the immediate precursor of cirrhosis. Two other studies, from the U.S. and Japan, demonstrated that chronic hepatitis appeared at about 10 years post-infection, cirrhosis at about 20 years, and HCC at about 30 years.

Since in many cases it is impossible to determine precisely the time of HCV infection, some authors and most practicing hepatologists evaluate the progression to cirrhosis from the time of patient presentation to a physician. In a typical progression, confirmed in at least one large study, 25% of patients would be cirrhotic within five years of presentation, and almost 50% would have cirrhosis within 10 years.

Older age at the time of infection, alcohol use, male gender, and HIV co-infection have been consistently associated with accelerated disease progression. Alcohol use is the only one of these risk factors that is modifiable. Fibrosis progression is not necessarily linear and may accelerate after the age of 50 years, irrespective of disease duration. Steatosis is also associated with more advanced fibrosis in HCV patients. While genotype is not associated with the rate of progression, possible risk factors for accelerated progression to cirrhosis are obesity and heterozygosity for hemochromatosis.

Liver histology provides the best tool to stratify an individual patient's risk of progressing to cirrhosis. Based on a model derived from the cross-sectional analysis of histologic data from more than 1,100 patients, HCV disease progression was categorized as slow, intermediate, or rapid. A third of patients are slow to fibrose and thus unlikely to develop cirrhosis during a 30-year period, another third would develop cirrhosis within 30 years, and the remaining third would show an intermediate rate of progression.

Baseline fibrosis at presentation has a good prognostic value. In an often cited U.S. study, 15 of 15 patients with severe baseline fibrosis progressed to cirrhosis within 10 years, whereas only 8 of 27 patients with mild fibrosis did so.

Patients with minimal fibrosis do not need to be screened for liver cancer, and may choose to defer treatment until a liver biopsy demonstrates progressing fibrosis. Such patients with fibrosis scores of stage 0 or 1 should have a follow-up liver biopsy within three to five years. Patients with stage 2 fibrosis need treatment in the near term, and patients with stage 3 or 4 fibrosis must be treated immediately and, if treatment fails, need to be aggressively treated as new therapies evolve. Approximately 20% of patients with cirrhosis will develop HCC.

The variability of individual responses further complicates the management of HCV infection. For example, even the development of cirrhosis is not necessarily fatal. Patients with compensated cirrhosis caused by HCV have a good intermediate-term prognosis.

In a 10-year longitudinal European study of nearly 400 individuals with HCV-related compensated cirrhosis, the cumulative probability of developing clinical decompensation was 20% at five years and 30% at 10 years. During the observation period, 13% of patients died; 70% of the deaths were from liver-related causes, such as HCC, liver failure, and bleeding. The actuarial survival of patients with compensated cirrhosis was 90% at five years and 80% at 10 years. One important conclusion of the study was that only patients who develop one of the complications of cirrhosis (their five-year survival rate was 50%) should be considered for liver transplantation.

A question of ultimate relevance to the success of the therapy for HCV is how these different clinical characteristics and potential outcomes influence the response to therapy.

Practice:

The primary goal of HCV therapy is the eradication of HCV in naïve patients with documented HCV viremia. This should be achieved as early as possible before the onset of fibrosis but should also be attempted in patients with fibrosis regardless of the stage of its advancement. Secondary goals, which must be achieved in the presence of fibrosis or cirrhosis, include slowing disease progression; improving histology; reducing risk of HCC; and improving health-related quality of life (QOL). The effect of therapy in clinical trials is measured as the SVR rate, that is, the proportion of patients with undetectable HCV RNA in serum at 24-week follow-up after the end of treatment. Long-term follow-up studies show that more than 95% of SVR patients remain free of detectable viremia for four to 10 years and that their liver histology improves over time.

The currently acceptable therapy for HCV is a combination of interferon and ribavirin. Conjugation of polyethylene glycol (PEG) to interferon--pegylated interferon--is the newest advance in the treatment of HCV patients. Pegylation increases the elimination half-life of interferon, providing improved efficacy with once-weekly dosing. SVR rates in patients infected with genotype 1 HCV have increased from 10-15% with interferon monotherapy to over 50% using the pegylated interferon-ribavirin combination. Patients infected with genotype 2 or 3 achieve SVR rates of 80% and more.

SVR rates of patients in whom treatment was begun in the presence of compensated cirrhosis remained lower than those of patients without cirrhosis (44% vs. 57% in a randomized, multi-center trial). Yet, preliminary results from several large studies in progress have shown that interferon has an effect on fibrogenesis and cirrhosis, both in responders and non-responders. Interferon decreases the rate of fibrosis progression and may cause fibrosis regression. It also significantly reduces the incidence of HCC compared with patients who remain untreated. Finally, pegylated interferon-ribavirin combination improved the health-related QOL in noncirrhotic patients with SVR and resulted in lasting improvement in cirrhotic patients with SVR, as measured using the SF-36 questionnaire.

Given the availability of this powerful combination, most hepatologists, including those at UI Hospitals and Clinics, would aggressively treat patients with moderate hepatitis C, bridging fibrosis, or cirrhosis. There is almost a consensus that HCV patients with normal histologic findings need not be treated if periodically followed up with liver biopsy. The intermediate group of patients with mild histologic findings, however, remains controversial because not all patients with chronic hepatitis C will progress to cirrhosis and some may wish to avoid treatment because of its potential side effects.

In those patients, it is still far from certain if watchful waiting with periodic liver biopsy would yield better long-term results than immediate therapy. Provided the current uncertainty, considerations of cost-effectiveness might help determine which of the two alternatives is preferable. A comprehensive cost-effectiveness analysis of existing clinical trials and published studies concluded that for patients with histologically mild hepatitis C, initial combination treatment reduces the future risk for cirrhosis, prolongs life, and is cost-effective, as compared with periodic liver biopsy management.

According to this study, over 20 years, biopsy every three years followed by treatment of moderate chronic hepatitis C or cirrhosis would avoid treatment in 50% of the cohort. It also would result in an 18% likelihood of cirrhosis. In comparison, the likelihood of cirrhosis after immediate antiviral therapy for mild chronic hepatitis C is 16%, while without antiviral therapy it is 27%. Immediate antiviral treatment should increase life expectancy by 1.0 quality-adjusted life-year compared with biopsy management. Over an average lifetime, biopsy management would result in six liver biopsies costing $6,200. Immediate antiviral treatment would cost $5,100 less than biopsy management because of savings related to biopsy and prevention of future hepatitis C-related morbidity. Thus, compared with biopsy management, immediate therapy is cost-effective and, compared with no antiviral therapy, it had a cost-effectiveness ratio of $7,000.

At UI Hospitals and Clinics, immediate therapy with pegylated interferon-ribavirin is considered in all newly diagnosed HCV patients except those who have minimal liver disease and a long standing HCV infection, in older patients, or in patients with a major non-liver related medical problems in addition to minimal liver disease.

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